Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation.

Dehmer, Thomas; HENEKA, Michael; Sastre, Magdalena; Dichgans, Johannes; Schulz, Jörg B

doi:10.1046/j.1471-4159.2003.02210.x

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Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation.

Dehmer, Thomas; HENEKA, Michael; Sastre, Magdalena et al.

2004 • In Journal of Neurochemistry, 88 (2), p. 494 - 501

Peer Reviewed verified by ORBi

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https://hdl.handle.net/10993/61678

DOI
10.1046/j.1471-4159.2003.02210.x

PubMed
14690537

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Keywords :

Enzyme Inhibitors; I-kappa B Proteins; NF-kappa B; Nfkbia protein, mouse; Thiazolidinediones; NF-KappaB Inhibitor alpha; Nitric Oxide Synthase; Nitric Oxide Synthase Type II; Nos2 protein, mouse; Pioglitazone; Animals; Brain/drug effects; Brain/metabolism; Disease Models, Animal; Enzyme Activation/drug effects; Enzyme Activation/physiology; Enzyme Inhibitors/pharmacology; Enzyme Inhibitors/therapeutic use; I-kappa B Proteins/biosynthesis; MPTP Poisoning/enzymology; MPTP Poisoning/metabolism; MPTP Poisoning/prevention & control; Male; Mice; Mice, Inbred C57BL; NF-kappa B/antagonists & inhibitors; NF-kappa B/metabolism; Nitric Oxide Synthase/antagonists & inhibitors; Nitric Oxide Synthase/metabolism; Thiazolidinediones/pharmacology; Thiazolidinediones/therapeutic use

Abstract :

[en] Inflammation has been implicated in the pathogenesis of Parkinson's disease (PD). In the chronic 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) model of PD, inducible NO synthase (iNOS) derived nitric oxide (NO) is an important mediator of dopaminergic cell death. Ligands of the peroxisome proliferator-activated receptor (PPAR) exert anti-inflammatory effects. We here investigated whether pioglitazone, a PPARgamma agonist, protected mice from MPTP-induced dopaminergic cell loss, glial activation, and loss of catecholamines in the striatum. As shown by western blot, PPARgamma was expressed in the striatum and the substantia nigra of vehicle- and MPTP-treated mice. Oral administration of 20 mg/(kg day) of pioglitazone protected tyrosine hydroxylase (TH)-positive substantia nigra neurons from death induced by 5 x 30 mg/kg MPTP. However, the decrease of dopamine in the striatum was only partially prevented. In mice treated with pioglitazone, there were a reduced activation of microglia, reduced induction of iNOS-positive cells and less glial fibrillary acidic protein positive cells in both striatum and substantia nigra pars compacta. In addition, treatment with pioglitazone almost completely blocked staining of TH-positive neurons for nitrotyrosine, a marker of NO-mediated cell damage. Because an increase in inhibitory protein-kappa-Balpha (IkappaBalpha) expression and inhibition of translocation of the nuclear factor kappaB (NFkappaB) subunit p65 to the nucleus in dopaminergic neurons, glial cells and astrocytes correlated with the protective effects of pioglitazone, our results suggest that pioglitazone sequentially acts through PPARgamma activation, IkappaBalpha induction, block of NFkappaB activation, iNOS induction and NO-mediated toxicity. In conclusion, treatment with pioglitazone may offer a treatment opportunity in PD to slow the progression of disease that is mediated by inflammation.

Disciplines :

Neurology

Author, co-author :

Dehmer, Thomas; Neurodegeneration Laboratory, Center of Neurology and Hertie Institute for Clinical Brain Research, University of Tübingen, Tübingen, Germany

HENEKA, Michael ; University of Tübingen, Tübingen, Germany. > Neurodegeneration Laboratory, Center of Neurology and Hertie Institute for Clinical Brain Research

Sastre, Magdalena

Dichgans, Johannes

Schulz, Jörg B

External co-authors :

yes

Language :

English

Title :

Protection by pioglitazone in the MPTP model of Parkinson's disease correlates with I kappa B alpha induction and block of NF kappa B and iNOS activation.

Publication date :

January 2004

Journal title :

Journal of Neurochemistry

ISSN :

0022-3042

eISSN :

1471-4159

Publisher :

Blackwell Publishing Ltd, England

Volume :

Issue :

Pages :

494 - 501

Peer reviewed :

Peer Reviewed verified by ORBi

Additional URL :

https://api.wiley.com/onlinelibrary/tdm/v1/articles/10.1046%2Fj.1471-4159.2003.02210.x

Available on ORBilu :

since 22 July 2024

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